The woodland has a number of blogs in relation to ‘therapy resistant melancholy’ taking a look at a variety of subjects from the affected person expertise to the associated fee effectiveness of interventions equivalent to long run psychoanalytic psychotherapy.
I put therapy resistant melancholy (TRD) in italics above as you might be stunned to know that there isn’t a consensus on its definition, which in flip signifies that the incidence charges range and there are not any constant medical pointers in relation to therapy (Gabriel et al 2023).
The US Meals and Drug Administration and the European Medicines Company have adopted essentially the most used definition of TRD (insufficient response to a minimal of two antidepressants regardless of adequacy of the therapy trial and adherence to therapy). It’s presently estimated that not less than 30% of individuals with melancholy meet this definition and so the burden of this side of melancholy isn’t insignificant (McIntyre R et al 2023).
The Maudsley Prescribing Pointers (Taylor et al 2021) first selection choices for administration of TRD embody augmentation with lithium and quetiapine. This weblog appears on the new randomised managed trial by Prof Tony Cleare et al, printed as we speak in The Lancet Psychiatry, immediately evaluating the medical and price effectiveness of the 2. This paper is especially attention-grabbing because the trial (the LQD research (Lithium versus Quetiapine in Despair)) has a for much longer observe up interval than earlier research, enabling a ‘actual life’ comparability.
The LQD research, printed as we speak within the Lancet Psychiatry compares the medical and price effectiveness of lithium and quetiapine for therapy resistant melancholy.
Strategies
So, this trial is a *takes a deep breath* “section 4, pragmatic, open label, parallel-group, randomised managed superiority trial, evaluating the medical effectiveness and price effectiveness of lithium versus quetiapine augmentation of antidepressant treatment in contributors with treatment-resistant melancholy.”. Let me break that down for you:
- Part 4: treatment is permitted and being utilized in apply. These trials have a look at long run security and effectiveness in apply
- Pragmatic: trying on the effectiveness of medicines in actual life conditions
- Open label: contributors and researchers know which therapy the contributors are receiving (non-blinded research)
- Parallel group: two energetic therapy teams, that are then in contrast
- Randomised managed superiority trial: contributors have been randomly assigned to therapy teams and reviewed as to which therapy performs higher.
Medical effectiveness course of: Following random allocation to therapy, trial clinicians may resolve whether or not to proceed with prescription of the allotted treatment primarily based on pre-prescribing security checks and medical judgement. All contributors, no matter trial treatment standing, have been adopted up over 12 months until they actively withdrew.
The first outcomes have been:
- The Fast Stock of Depressive Symptomatology (QIDS-SR) , used as a weekly measure of temper state and
- Time to discontinuation of therapy.
Weekly information on QIDS-SR, Work and Social Adjustment Scale (WSAS) and trial treatment standing have been collected through an internet platform, True Colors.
Value effectiveness course of: The Shopper Service Receipt Stock was used at baseline, 8, 26, and 52 weeks. This instrument collects information on health-care service use, together with the quantity and length of contacts with main and secondary health-care providers. High quality-Adjusted Life Years (QALYs) have been used to measure well being advantages.
Outcomes
Over a 4.5 yr interval (Dec 2016 to July 2021) 262 sufferers have been screened for eligibility from 6 NHS Trusts throughout England. The inclusion standards included:
- ≥ 18 years
- Below the care of a GP or psychological well being service
- Present depressive episode assembly DSM-5 standards for main depressive dysfunction (single or recurrent episode)
- Rating of ≥ 14 on the 17 merchandise Hamilton Despair Score Scale
- Insufficient response of the present episode to 2 or extra antidepressants, prescribed for not less than 6 weeks at therapeutic dose
- Present antidepressant therapy unchanged and at therapeutic dose for not less than 6 weeks; and
- Have been in a position to present written knowledgeable consent
Exclusion standards included (however not restricted to)
- Analysis of bipolar dysfunction or present psychosis
- Ample use of lithium or quetiapine of their present episode
- Present use of one other atypical antipsychotic.
There have been main, secondary and tertiary outcomes within the research. For this weblog I’ll deal with the first outcomes and notice any key outcomes from the secondary outcomes (tertiary outcomes weren’t included on this publication).
212 sufferers have been randomly assigned:
- 105 assigned to lithium; 21 didn’t obtain or provoke lithium however remained within the trial. 66 offered information at 52 week observe up
- 107 assigned to quetiapine; 12 didn’t obtain quetiapine however remained within the trial. 78 offered information at 52 week observe up
Medical effectiveness outcomes
Major outcomes
- Total burden of depressive symptom severity over 12 months
- Time to all trigger discontinuation
Members within the quetiapine group had a decrease total burden of depressive symptom severity than contributors within the lithium group over 12 months. The QIDS-SR information factors have been mapped over the yr and the world underneath the curve calculation used as a measure of depressive symptom burden. The world underneath the curve was smaller for Quetiapine: (space underneath the distinction curve –68.36 [95% CI –129.95 to –6.76]; p=0.0296).
Time to trial treatment discontinuation didn’t differ considerably between the 2 teams; the median time was:
- 365.0 days (Inter-Quartile Vary, IQR 57.0 to 365.0) within the quetiapine group
- 212.0 days (21.0 to 365.0) within the lithium group
- Adjusted hazard ratio [HR] 0.72 [95% CI 0.47 to 1.09]; p=0.1196.
Given the broad IQR and huge discrepancy between the respective medians, we should take into account this “absence of proof” reasonably than “proof of absence”.
By way of secondary outcomes, contributors within the quetiapine group had considerably decrease MADRS (p=0.0435) and WSAS scores (p=0.0071) at week 52 than contributors within the lithium group. No vital variations have been famous within the different secondary outcomes which included bodily well being parameters and hostile occasions (see paper for full particulars). An attention-grabbing detrimental consequence was that no weight achieve was noticed throughout time within the quetiapine group.
Value effectiveness outcomes
In contrast with lithium, quetiapine was dominant. Prices have been decrease whereas advantages have been larger.
From an NHS and private social providers perspective, quetiapine was related to decrease price and bigger achieve in QALYs, than lithium. The incremental internet well being good thing about Quetiapine was 0.097 over lithium (with any constructive consequence indicating choice to the in contrast various). Extra price effectiveness evaluation can be found within the appendices of the paper which define that quetiapine is essentially the most cost-effective possibility in accordance with the NICE willingness-to-pay threshold.
The quetiapine therapy group had a decrease total burden of depressive symptomatology than lithium.
Conclusions
The authors concluded that:
our findings recommend a reasonable and clinically related good thing about quetiapine over lithium for long-term therapy of contributors with treatment-resistant melancholy.
And this research:
…extends the earlier discovering that quetiapine is non-inferior to lithium over the brief time period and recommend superiority over the long term.
In comparison with lithium, quetiapine is essentially the most cost-effective possibility in relation to the NICE willingness-to-pay threshold.
Strengths and limitations
This paper has some actual strengths in that its principal goal was to imitate real-life medical selections and sufferers. There was lived expertise involvement in designing and working the trial and affected person and public involvement members have been supportive of the weekly QIDS-SR assessments to supply a greater indication of the course and long-term length of final result for what generally is a fluctuating medical course in therapy resistant melancholy (TRD). Following sufferers up for 1 yr was a giant plus.
As a result of nature of the trial, clinicians weren’t blind to allocation, nonetheless the authors report that ‘clinician rated final result measures have been assessed by masked raters and statisticians have been unaware of group allocation till the information evaluation section’ to attempt to scale back bias as a lot as doable.
With each trial there can be limitations and this paper isn’t any exception. Having clinician judgement as as to if the allotted medication is prescribed probably introduces allocation bias.
The affected person teams have been randomised in accordance with diploma of therapy resistance (failure of two versus three or extra antidepressant therapies within the present episode) they usually used ‘block randomisation with randomly various block sizes’, nonetheless inside the outcomes there isn’t a reference as to what number of have been in every group or whether or not the outcomes correlated to this.
A lot of the information relied on self-reports. Though this methodology was developed in partnership with affected person teams, the burden could have contributed to attrition.
In the course of the trial, the pattern dimension was diminished from 276 to 214 as a result of challenges with recruitment. Energy calculations have been accomplished and have been 80% for time to discontinuation and 96.5% energy with an impact dimension of 0.38. It’s nonetheless unclear if the discontinuation charges, impact sizes and attrition charges have been modified from the unique planning when calculating these. There seemed to be probably regarding gaps within the 52 week assortment information, extra so for lithium (37% for the lithium group and 27% for the Quetiapine group) and the authors notice substantial lacking information for among the secondary outcomes.
Total, there was numerous attrition, which ought to warning our interpretation of those outcomes. The intention to deal with evaluation solely included 66/104 and 78/107 of the lithium and quetiapine sufferers respectively. The totally different ranges of attrition in every group could imply that we’re now not evaluating like with like throughout the teams.
Lastly, the inhabitants examined was predominantly white (89%) which is able to restrict the flexibility for generalisation to all populations.
Mimicking actual life medical apply over a yr comes with it’s personal limitations.
Implications for apply
Sufferers who’ve melancholy which is ‘troublesome to deal with’ are ‘clinically difficult’ and undergo a big burden from the illness. Each lithium and quetiapine are widespread choices for augmentation and this paper highlights that quetiapine may very well be extra efficacious and price efficient than lithium. The size of observe up of the research makes this encouraging and positively value contemplating. The facility of the research and the reasonably heterogeneous group of severity could restrict leaping to a right away use of quetiapine over lithium, but when there was future replication of this research and outcomes, then that will surely be convincing.
The authors are clear although that Lithium stays an efficient therapy possibility. It’s possible that the medicines can have totally different advantages for various individuals (e.g. considerations in relation to sleep, urge for food, nervousness) and so therapy must be tailor-made to those wants. Nonetheless, if lithium and quetiapine are equally acceptable then quetiapine may pip lithium to the put up.
Having clear medical pointers in relation to methods for ‘troublesome to deal with’ melancholy and/or when it turns into ‘therapy resistant’, appears a precedence in order that future analysis will be evaluating apples with apples.
On the time of scripting this, there’s a complicating consider that there’s a nationwide scarcity of modified launch quetiapine and we’re having to maneuver sufferers onto speedy launch Quetiapine which has a distinct aspect impact profile and will not produce outcomes replicable to the research.
Quetiapine could pip lithium to the put up if on a good area.
The non-public affect of therapy resistant melancholy can’t be underestimated and I’m certain they’d agree with the phrases of Bon Jovi ‘I simply need to dwell whereas I’m alive…it’s my life’.
Assertion of pursuits
I’ve no battle of pursuits to reveal
Hyperlinks
Major paper
Anthony J Cleare, Jess Kerr-Gaffney, Kimberley Goldsmith, Zohra Zenasni, Nahel Yaziji, Huajie Jin, Alessandro Colasanti, John R Geddes, David Kessler, R Hamish McAllister-Williams, Allan H Younger, Alvaro Barrera, Lindsey Marwood, Rachael W Taylor, Helena Tee, and on behalf of he LQD Examine Group. (2025) Medical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant melancholy in England: a practical, open-label, parallel-group, randomised managed superiority trial. The Lancet Psychiatry 2025. DOI: 10.1016/S2215-0366(25)00028-8
Different references
Gabriel FC et al (2023) Pointers’ suggestions for the treatment-resistant melancholy: A scientific evaluation of their high quality. PLoS ONE 18(2): e0281501.
McIntyre RS, et al (2023) Therapy-resistant melancholy: definition, prevalence, detection, administration, and investigational interventions. World Psychiatry. (2023) 22, no. 3, 394–412.
Taylor, David M, et al. The Maudsley Prescribing Pointers in Psychiatry. 14th ed., John Wiley & Sons, 2021 pg 318-319.
